MASP-2 Deficient Mammals for Complement Study
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Solution Overview
Problem
Current therapies lack effective drugs that specifically inhibit complement activation, which contributes to various disease states such as myocardial infarction, stroke, and transplant rejection, highlighting the need for targeted complement inhibitory agents.
Innovation Solution
Creation of genetically modified non-human mammals and cells deficient in MASP-2, a key component of the lectin complement pathway, to serve as models for studying lectin pathway deficiency and potential therapeutic tools for disorders like reperfusion injury and myocardial infarction, along with the production of antibodies against MASP-2 for therapeutic use.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If genetically modified mammals deficient in MASP-2 are created to study lectin pathway deficiency, then the ability to study complement activation mechanisms is improved, but the complexity of genetic modification and model creation increases
Solution Approach 1:
The patent applies the extraction principle by removing the MASP-2 gene component from the complement system through targeted gene deletion. This creates a simplified model where the lectin pathway is specifically disabled, allowing researchers to study complement activation mechanisms by isolating and removing the problematic element (MASP-2) rather than attempting to control or regulate it.
Solution Approach 2:
The patent uses embryonic stem cells as an intermediary medium to achieve the genetic modification. By modifying MASP-2 deficiency in embryonic stem cells first, then injecting these modified cells into blastocysts to create chimeric animals, the complex genetic modification process is broken down into manageable steps using the embryonic stem cell line as a mediator between the targeting construct and the final mammal model.
2Adaptability or versatility
If antibodies against MASP-2 are produced for therapeutic use to inhibit complement activation, then the potential for treating inflammatory diseases is improved, but the complexity of antibody production and validation increases
Solution Approach 1:
The patent applies the self-service principle by using the MASP-2 deficient mammals themselves to produce the therapeutic antibodies. The modified animals serve dual purposes: they are both the disease model for studying complement activation and the source for generating anti-MASP-2 antibodies through immunization, eliminating the need for separate antibody production systems.
Solution Approach 2:
The patent makes the MASP-2 deficient mammal model multi-functional by using it for both research purposes (studying lectin pathway deficiency and complement activation) and therapeutic development (producing antibodies for treating inflammatory diseases). This single model system serves multiple functions in the research and development pipeline.
3Loss of information
If MASP-2 deficient models are used to study disease mechanisms, then the understanding of lectin pathway role in health and disease is improved, but the time and resources required for model development increase
Solution Approach 1:
The patent applies preliminary action by first establishing the MASP-2 deficient embryonic stem cell line before creating the mammal models. This preliminary genetic modification work in cell culture allows for validation of the targeting construct and confirmation of MASP-2 deficiency before the time-consuming process of generating chimeric animals and breeding programs begins, saving overall development time.
Data Source
AI summary
Genetically modified mammals are described which lack the mannan binding lectin associated serine protease MASP-2, together with methods and constructs for their production. Such mammals are useful as models for disorders of the complement system, and in the identification of treatments for such disorders. Also described are mammals which lack the associated protein MAp19; such mammals may also lack MASP-2.